Ewing's sarcoma is an aggressive and highly metastatic malignancy first described by James Ewing in 1921. It arises in and around the bones of the extremities and central skeleton, but may also arise in the soft tissues as “extraosseous Ewing's.” Ewing's sarcoma primarily affects children and young adults, predominantly those of European descent, with the highest rates of development occurring in white male adolescents.
Cells of Ewing's sarcoma appear as small, round, undifferentiated blue cells, and thus belongs to a class of tumors with a similar histologic appearance which includes rhabdomyosarcoma, neuroblastoma, and lymphoma. However, the cell of origin of Ewing's sarcoma is unknown. Most cases of Ewing's sarcoma have a recurrent chromosomal translocation, t(11;22)(q24;q12), that encodes a fusion protein, EWS/FLI (Dellatre et al., 1992). The FLI portion contains an ETS family DNA-binding domain while the EWS portion functions as a strong transcriptional activation domain (Dellatre et al., 1992; Lessnick et al., 1995; May et al., 1993a; May et al., 1993b). EWS/FLI is thus an aberrant transcription factor that dysregulates target genes involved in tumor development.
The diagnosis of Ewing's sarcoma is typically based on histologic criteria and associated expression of EWS/FLI. The majority of the translocations code for EWS/FLI. However, a minority of translocations encode fusions that are similar, but not identical to EWS/FLI. Consequently, molecular diagnostics that test for EWS/FLI, such as quantitative PCR, miss approximately 15% of Ewing's sarcoma cases. Immunohistochemistry is a more wide-spread and readily applied technique for diagnosis. The most specific and sensitive immunohistochemical marker for Ewing's sarcoma is CD99 expression. However, CD99 expression is an imperfect marker, as some similar tumors can express CD99.
Treatment of Ewing's sarcoma involves therapies targeting the primary tumor with surgery, radiation, or both. However, in the absence of additional therapy, most patients will relapse with distant metasteses. Current treatment includes systemic chemotherapy to eradicate micrometastatic deposits. These regimens include doxorubicin, vincristine, and cyclophosphamide, alternating with etoposide and ifosfamide. However, these drugs act with little specificity for Ewing's sarcoma and have significant side effects.
Overall, the treatment of Ewing's sarcoma remains problematic. Patients with metastatic disease at presentation have long-term cure rate of less than 30%. In the absence of metastatic disease, the cure rate for Ewing's sarcoma is only 50% to 70%. Quick and early identification can lead to intervention with appropriate treatments with potentially better outcomes.